Healing Hearts: Co-dependent FGF-VEGF mediation of coronary vasculature Open Access

Jiao, Cheng (Spring 2020)

Permanent URL: https://etd.library.emory.edu/concern/etds/x920fz06f?locale=en
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Abstract

Unlike most vertebrates, following a myocardial infarction, zebrafish have the remarkable ability to regenerate their hearts instead of forming permanent scar tissue. Previous studies have indicated that to support this replenishment of lost tissue, there needs to be subsequent rapid revascularization of the damaged area. Here, I show that zebrafish coronary vasculature is modulated by fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) co-dependent pathways. By observing juvenile delta;EGFP zebrafish, I was able to demonstrate that growth factor pathways other than VEGF have a role in vessel development and rapid coronary vascularization. Analysis of FGF and VEGF inhibitory assays indicate that both angiogenic pathways are necessary for the upkeep of the coronary vasculature during adulthood. Investigations in the past have previously shown that FGF signaling can promote VEGF enhancer activity and upregulate VEGFR expression. Likewise, my results demonstrate a temporal disparity between FGF and VEGF inhibition that is indicative of some relationality between the two pathways. When FGF was blocked, it potentially had less initial effect upon the endothelial cells. But due to FGF-VEGF crosstalk, the FGF inhibition could also downregulate VEGF expression, leading to the observed increased effect upon coronary vessels seen later on. Importantly, the combinational inhibition of VEGFR and its ligand suggests that there is a possible impedance of FGF-directed rescue of VEGF expression because vegfa pulldown makes the additional VEGFR receptors meaningless. Additionally, the implications of this FGF-VEGF signal transduction can directly impact heart regeneration because VEGF was reaffirmed to be an essential factor in vascular development after cardiac injury. Altogether, my findings about the interaction of angiogenic growth factor systems provide for a more holistic approach toward investigating the interplay between revascularization and subsequent cardiac regeneration. 

Table of Contents

I.  Introduction and Literature Review………………………………………………….. 1

A.   Pathophysiology of human myocardial infarction……….…………………….… 1

B.    Heart regeneration in vertebrates………………………………………………… 3

C.    Zebrafish cardiac injury response………………………………………………... 4

D.   Importance of coronary revascularization in regeneration………………………. 6

E.    VEGF and FGF communication and potential combinational impact……………. 8

II.                Materials and Methods……………………………………………………………… 10

III.             Results………………………………………………………………………………. 14

A.   Organogenesis promote the growth of new vessels from pre-existing………….. 14

B.    Non-VEGF growth factors can modulate developmental angiogenesis ………… 16

C.    Growth factor inhibition has differential spatiotemporal effects on adult heart…. 17

D.   Maintenance of adult vasculature dependent on the FGF-VEGF coordination…. 20

E.    VEGF mediates rapid revascularization following heart injury…………………. 21

IV.             Discussion..…………………………………………………………………………. 24

V.               References…………………………………………………………………………... 26

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